Machado Joseph disease (MJD), or spinocerebellar ataxia-3 (SCA-3), is the most common dominant spinocerebellar ataxia. MJD/SCA-3 is hereditary, neurodegenerative, and caused by glutamine expansion in the protein ataxin-3 (mutant ataxin-3) possibly resulting in a gain of function. The applicant's aim is to understand the mechanism(s) of neurodegeneration in MJD/SCA-3. SPECIFIC Aim #1: To facilitate the study MJD/SCA-3, the investigator will develop a mouse model. Transgenic mice were generated expressing human full-length mutant ataxin-3. The investigator will define the time course of behavior abnormalities and age at death. There will be a search for evidence of neurodegeneration. SPECIFIC Aim #2: The investigator will test the hypothesis that neurodegeneration is caused by a proteolytic event forming a toxic fragment. A small form of mutant ataxin-3 in transgenic mouse brain was identified. Its brain distribution will be determined. The putative cleavage site will be identified. The investigator will study transgenic mice expressing mutant ataxin-3 with the putative cleavage site mutated. SPECIFIC Aim #3: The applicant's aim is to test the hypothesis that mutant ataxin-3 interactors cause neurodegeneration. A mutant ataxin-3 interactor using the yeast-two-hybrid method was identified. The investigator will determine if the interaction occurs in mammalian cells and search/characterize for new interactors.